tbuckley/cabot-search huggingface dataset:
Not Quite Lost in Translation: Mistranslation Alters Adaptive Landscape Topography and the Dynamics of Evolution
Authors: Michael Schmutzer, Andreas Wagner
Journal: Molecular Biology and Evolution (2023)

Abstract Mistranslation—the erroneous incorporation of amino acids into nascent proteins—is a source of protein variation that is orders of magnitude more frequent than DNA mutation. Like other sources of nongenetic variation, it can affect adaptive evolution. We study the evolutionary consequences of mistranslation with experimental data on mistranslation rates applied to three empirical adaptive landscapes. We find that mistranslation generally flattens adaptive landscapes by reducing the fitness of high fitness genotypes and increasing that of low fitness genotypes, but it does not affect all genotypes equally. Most importantly, it increases genetic variation available to selection by rendering many neutral DNA mutations nonneutral. Mistranslation also renders some beneficial mutations deleterious and vice versa. It increases the probability of fixation of 3–8% of beneficial mutations. Even though mistranslation increases the incidence of epistasis, it also allows populations evolving on a rugged landscape to evolve modestly higher fitness. Our observations show that mistranslation is an important source of nongenetic variation that can affect adaptive evolution on fitness landscapes in multiple ways.
Disulfiram with Cu<sup>2+</sup> alleviates dextran sulfate sodium-induced ulcerative colitis in mice
Authors: Wei Zhou, Hua Zhang, Lihua Huang, Chuankai Sun, Yuhan Yue, Xiaolei Cao, Hongling Jia, Chunyue Wang, Yunfei Gao
Journal: Theranostics (2023)

Background: Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug for chronic alcohol addiction, has anti-inflammatory effects that help prevent various cancers, and Cu 2+ can enhance the effects of DSF.Inflammatory bowel diseases (IBD) are characterized by chronic or recurrent relapsing gastrointestinal inflammation.Many drugs targeting the immune responses of IBD have been developed, but their application has many problems, including side effects and high costs.Therefore, there is an urgent need for new drugs.In this study, we investigated the preventive effects of DSF+Cu 2+ on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice.Methods: The anti-inflammatory effects were investigated using the DSS-induced colitis mouse model and lipopolysaccharide (LPS)-induced macrophages.DSS-induced TCRβ -/-mice were used to demonstrate the effect of DSF in conjunction with Cu 2+ on CD4 + T cell-secreted interleukin 17 (IL-17).In addition, the effect of DSF+Cu 2+ on intestinal flora was studied by 16S rRNA microflora sequencing.Results: DSF and Cu 2+ could significantly reverse the symptom of DSS-induced UC in mice, such as weight loss, disease activity index score, colon length shortening, and reversal of colon pathological changes.DSF and Cu 2+ could inhibit colonic macrophage activation by blocking the nuclear factor kappa B (NF-κB) pathway, reducing nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3)-inflammasome-derived interleukin 1 beta (IL-1β) secretion and caspase-1 (CASP1) activation, and decreasing IL-17 secretion by CD4 + T cells.Moreover, the treatment of DSF and Cu 2+ could protect the intestinal barrier by reversing the expression of tight junction proteins, zonula occluden-1 (ZO-1), occludin, and mucoprotein-2 (MUC2).Additionally, DSF+Cu 2+ could reduce the abundance of harmful bacteria and increase beneficial bacteria in the intestinal tract of mice, effectively improving intestinal microecology. Conclusion:Our study evaluated the effect of DSF+Cu 2+ on the immune system and gut microbiota in colonic inflammation and highlighted its potential to treat UC in the clinic.
Automatic Surgical Skill Assessment System Based on Concordance of Standardized Surgical Field Development Using Artificial Intelligence
Authors: Takahiro Igaki, Daichi Kitaguchi, Hiroki Matsuzaki, Kei Nakajima, Shigehiro Kojima, Hiro Hasegawa, Nobuyoshi Takeshita, Yusuke Kinugasa, Masaaki Ito
Journal: JAMA Surgery (2023)

Automatic surgical skill assessment with artificial intelligence (AI) is more objective than manual video review-based skill assessment and can reduce human burden. Standardization of surgical field development is an important aspect of this skill assessment.
Fixed Allele Differences Associated With the Centromere Reveal Chromosome Morphology and Rearrangements in a Reptile (<i>Varanus acanthurus</i> BOULENGER)
Authors: Jason Dobry, Zexian Zhu, Qi Zhou, Erik Wapstra, Janine E Deakin, Tariq Ezaz
Journal: Molecular Biology and Evolution (2023)

Abstract Chromosome rearrangements are often implicated with genomic divergence and are proposed to be associated with species evolution. Rearrangements alter the genomic structure and interfere with homologous recombination by isolating a portion of the genome. Integration of multiplatform next-generation DNA sequencing technologies has enabled putative identification of chromosome rearrangements in many taxa; however, integrating these data sets with cytogenetics is still uncommon beyond model genetic organisms. Therefore, to achieve the ultimate goal for the genomic classification of eukaryotic organisms, physical chromosome mapping remains critical. The ridge-tailed goannas (Varanus acanthurus BOULENGER) are a group of dwarf monitor lizards comprised of several species found throughout northern Australia. These lizards exhibit extreme divergence at both the genic and chromosomal levels. The chromosome polymorphisms are widespread extending across much of their distribution, raising the question if these polymorphisms are homologous within the V. acanthurus complex. We used a combined genomic and cytogenetic approach to test for homology across divergent populations with morphologically similar chromosome rearrangements. We showed that more than one chromosome pair was involved with the widespread rearrangements. This finding provides evidence to support de novo chromosome rearrangements have occurred within populations. These chromosome rearrangements are characterized by fixed allele differences originating in the vicinity of the centromeric region. We then compared this region with several other assembled genomes of reptiles, chicken, and the platypus. We demonstrated that the synteny of genes in Reptilia remains conserved despite centromere repositioning across these taxa.
Extended-Release Buprenorphine Receives FDA Green Light
Authors: Emily Harris
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline
Authors: Felix Sahm, Sebastian Brandner, Luca Bertero, David Capper, Pim J French, Dominique Figarella-Branger, Felice Giangaspero, Christine Haberler, Monika E Hegi, Bjarne W Kristensen, Kathreena M Kurian, Matthias Preusser, Bastiaan B J Tops, Martin van den Bent, Wolfgang Wick, Guido Reifenberger, Pieter Wesseling
Journal: Neuro-Oncology (2023)

Abstract In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types. For those tumors, an integrated, “histomolecular” diagnosis is required. A variety of approaches exists for determining the status of the underlying molecular markers. The present guideline focuses on the methods that can be used for assessment of the currently most informative diagnostic and prognostic molecular markers for the diagnosis of gliomas, glioneuronal and neuronal tumors. The main characteristics of the molecular methods are systematically discussed, followed by recommendations and information on available evidence levels for diagnostic measures. The recommendations cover DNA and RNA next-generation-sequencing, methylome profiling, and select assays for single/limited target analyses, including immunohistochemistry. Additionally, because of its importance as a predictive marker in IDH-wildtype glioblastomas, tools for the analysis of MGMT promoter methylation status are covered. A structured overview of the different assays with their characteristics, especially their advantages and limitations, is provided, and requirements for input material and reporting of results are clarified. General aspects of molecular diagnostic testing regarding clinical relevance, accessibility, cost, implementation, regulatory, and ethical aspects are discussed as well. Finally, we provide an outlook on new developments in the landscape of molecular testing technologies in neuro-oncology.
Cisplatin attenuates taste cell homeostasis and induces inflammatory activation in the circumvallate papilla
Authors: Wenwen Ren, Xudong Cha, Rui Xu, Tianyu Wang, Caiquan Liang, Janice Chou, Xiujuan Zhang, Fengzhen Li, Shenglei Wang, Boyu Cai, Peihua Jiang, Hong Wang, Huanhai Liu, Yiqun Yu
Journal: Theranostics (2023)

Rationale: Gustation is important to several biological functions in mammals.However, chemotherapy drugs often harm taste perception in cancer patients, while the underlying mechanism is still unclear for most drugs and there is no effective way to restore taste function.This study investigated the effects of cisplatin on the taste cell homeostasis and gustatory function.Methods: We used both mice and taste organoid models to study the effect of cisplatin on taste buds.Gustometer assay, gustatory nerve recording, RNA-Sequencing, quantitative PCR, and immunohistochemistry was performed to analyze the cisplatin-induced alteration in taste behavior and function, transcriptome, apoptosis, cell proliferation and taste cell generation.Results: Cisplatin inhibited proliferation and promoted apoptosis in the circumvallate papilla, leading to significant impairment in taste function and receptor cell generation.The transcriptional profile of genes associated with cell cycle, metabolic process and inflammatory response was significantly altered after cisplatin treatment.Cisplatin inhibited growth, promoted apoptosis, and deferred taste receptor cell differentiation in taste organoids.LY411575, a γ-secretase inhibitor, reduced the number of apoptotic cells and increased the number of proliferative cells and taste receptor cells, potentially suggesting as a taste tissue protective agent against chemotherapy.LY411575 treatment could offset the increased number of Pax1 + or Pycr1 + cells induced by cisplatin in the circumvallate papilla and taste organoids. Conclusion:This study highlights the inhibitory effects of cisplatin on taste cell homeostasis and function, identifies critical genes and biological processes regulated by chemotherapy, and proposes potential therapeutic targets and strategy for taste dysfunction in cancer patients.
Cardiac-specific BACH1 ablation attenuates pathological cardiac hypertrophy by inhibiting the Ang II type 1 receptor expression and the Ca2+/CaMKII pathway
Authors: Xiangxiang Wei, Jiayu Jin, Jian Wu, Yunquan He, Jieyu Guo, Zhaohua Yang, Liang Chen, Kui Hu, Liliang Li, Mengping Jia, Qinhan Li, Xiaoyu Lv, Fei Ge, Siyu Ma, Huijie Wu, Xiuling Zhi, Xinhong Wang, Lindi Jiang, Elena Osto, Jianyi Zhang, Dan Meng
Journal: Cardiovascular Research (2023)

Abstract Aims BACH1 is up-regulated in hypertrophic hearts, but its function in cardiac hypertrophy remains largely unknown. This research investigates the function and mechanisms of BACH1 in the regulation of cardiac hypertrophy. Methods and results Male cardiac-specific BACH1 knockout mice or cardiac-specific BACH1 transgenic (BACH1-Tg) mice and their respective wild-type littermates developed cardiac hypertrophy induced by angiotensin II (Ang II) or transverse aortic constriction (TAC). Cardiac-specific BACH1 knockout in mice protected the hearts against Ang II- and TAC-induced cardiac hypertrophy and fibrosis, and preserved cardiac function. Conversely, cardiac-specific BACH1 overexpression markedly exaggerated cardiac hypertrophy and fibrosis and reduced cardiac function in mice with Ang II- and TAC-induced hypertrophy. Mechanistically, BACH1 silencing attenuated Ang II- and norepinephrine-stimulated calcium/calmodulin-dependent protein kinase II (CaMKII) signalling, the expression of hypertrophic genes, and hypertrophic growth of cardiomyocytes. Ang II stimulation promoted the nuclear localization of BACH1, facilitated the recruitment of BACH1 to the Ang II type 1 receptor (AT1R) gene promoter, and then increased the expression of AT1R. Inhibition of BACH1 attenuated Ang II-stimulated AT1R expression, cytosolic Ca2+ levels, and CaMKII activation in cardiomyocytes, whereas overexpression of BACH1 led to the opposite effects. The increased expression of hypertrophic genes induced by BACH1 overexpression upon Ang II stimulation was suppressed by CaMKII inhibitor KN93. The AT1R antagonist, losartan, significantly attenuated BACH1-mediated CaMKII activation and cardiomyocyte hypertrophy under Ang II stimulation in vitro. Similarly, Ang II-induced myocardial pathological hypertrophy, cardiac fibrosis, and dysfunction in BACH1-Tg mice were blunted by treatment with losartan. Conclusion This study elucidates a novel important role of BACH1 in pathological cardiac hypertrophy by regulating the AT1R expression and the Ca2+/CaMKII pathway, and highlights potential therapeutic target in pathological cardiac hypertrophy.
Trajectories of renal biomarkers and new‐onset heart failure in the general population: Findings from the <scp>PREVEND</scp> study
Authors: Ryoto Sakaniwa, Jasper Tromp, Koen W. Streng, Navin Suthahar, Lyanne M. Kieneker, Douwe Postmus, Hiroyasu Iso, Ron T. Gansevoort, Stephan J.L. Bakker, Hans L. Hillege, Rudolf A. de Boer, Biniyam G. Demissei
Journal: European Journal of Heart Failure (2023)

Renal dysfunction is one of the most critical risk factors for developing heart failure (HF). However, the association between repeated measures of renal function and incident HF remains unclear. Therefore, this study investigated the longitudinal trajectories of urinary albumin excretion (UAE) and serum creatinine and their association with new-onset HF and all-cause mortality.Using group-based trajectory analysis, we estimated trajectories of UAE and serum creatinine in 6881 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study and their association with new-onset HF and all-cause death during the 11-years of follow-up. Most participants had stable low UAE or serum creatinine. Participants with persistently higher UAE or serum creatinine were older, more often men, and more often had comorbidities, such as diabetes, a previous myocardial infarction or dyslipidaemia. Participants with persistently high UAE had a higher risk of new-onset HF or all-cause mortality, whereas stable serum creatinine trajectories showed a linear association for new-onset HF and no association with all-cause mortality.Our population-based study identified different but often stable longitudinal patterns of UAE and serum creatinine. Patients with persistently worse renal function, such as higher UAE or serum creatinine, were at a higher risk of HF or mortality.
Efficiency of tofacitinib in refractory interstitial lung disease among anti-MDA5 positive juvenile dermatomyositis patients
Authors: Yuan Xue, Junmei Zhang, Jianghong Deng, Weiying Kuang, Jiang Wang, Xiaohua Tan, Chao Li, Shipeng Li, Caifeng Li
Journal: Annals of the Rheumatic Diseases (2023)
Venous Thromboembolism in Patients With Bullous Pemphigoid
Authors: Maria C. Schneeweiss, Joseph F. Merola, Richard Wyss, Jonathan I. Silverberg, Arash Mostaghimi
Journal: JAMA Dermatology (2023)

Studies have linked bullous pemphigoid (BP) with venous thromboembolism (VTE) across several data sources finding 6-fold to 15-fold increased incidence rates.
Melanonychia as a manifestation of chronic lead poisoning
Authors: Patrizia Elva Aguilar-Calderón, Mayra A Reyes-Soto, Emmanuel Sánchez-Meza, Alejandra Brown-Herrera, Jorge Ocampo-Candiani, Lucía T Fernández
Journal: British Journal of Dermatology (2023)

First-contact clinicians and dermatologists should be aware of melanonychia as an atypical presentation of chronic lead poisoning in high-risk groups.
Autocrine 17-β-Estradiol/Estrogen Receptor-α Loop Determines the Response to Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer
Authors: Dario P. Anobile, Iris C. Salaroglio, Fabrizio Tabbò, Sofia La Vecchia, Muhlis Akman, Francesca Napoli, Maristella Bungaro, Federica Benso, Elisabetta Aldieri, Paolo Bironzo, Joanna Kopecka, Francesco Passiglia, Luisella Righi, Silvia Novello, Giorgio V. Scagliotti, Chiara Riganti
Journal: Clinical Cancer Research (2023)

The response to immune checkpoint inhibitors (ICI) often differs between genders in non-small cell lung cancer (NSCLC), but metanalyses results are controversial, and no clear mechanisms are defined. We aim at clarifying the molecular circuitries explaining the differential gender-related response to anti-PD-1/anti-PD-L1 agents in NSCLC.We prospectively analyzed a cohort of patients with NSCLC treated with ICI as a first-line approach, and we identified the molecular mechanisms determining the differential efficacy of ICI in 29 NSCLC cell lines of both genders, recapitulating patients' phenotype. We validated new immunotherapy strategies in mice bearing NSCLC patient-derived xenografts and human reconstituted immune system ("immune-PDXs").In patients, we found that estrogen receptor α (ERα) was a predictive factor of response to pembrolizumab, stronger than gender and PD-L1 levels, and was directly correlated with PD-L1 expression, particularly in female patients. ERα transcriptionally upregulated CD274/PD-L1 gene, more in females than in males. This axis was activated by 17-β-estradiol, autocrinely produced by intratumor aromatase, and by the EGFR-downstream effectors Akt and ERK1/2 that activated ERα. The efficacy of pembrolizumab in immune-PDXs was significantly improved by the aromatase inhibitor letrozole, which reduced PD-L1 and increased the percentage of antitumor CD8+T-lymphocytes, NK cells, and Vγ9Vδ2 T-lymphocytes, producing durable control and even tumor regression after continuous administration, with maximal benefit in 17-β-estradiol/ERα highfemale immune-xenografts.Our work unveils that 17-β-estradiol/ERα status predicts the response to pembrolizumab in patients with NSCLC. Second, we propose aromatase inhibitors as new gender-tailored immune-adjuvants in NSCLC. See related commentary by Valencia et al., p. 3832.
Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO–College of American Pathologists Guideline Update
Authors: Antonio C. Wolff, Mark R. Somerfield, Mitchell Dowsett, M. Elizabeth H. Hammond, Daniel F. Hayes, Lisa M. McShane, Thomas J. Saphner, Patricia A. Spears, Kimberly H. Allison
Journal: Journal of Clinical Oncology (2023)

To update ASCO-College of American Pathologists (CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. The Panel is aware that a new generation of antibody-drug conjugates (ADCs) targeting the HER2 protein is active against breast cancers that lack protein overexpression or gene amplification.An Update Panel conducted a systematic literature review to identify signals for updating recommendations.The search identified 173 abstracts. Of five potential publications reviewed, none constituted a signal for revising existing recommendations.The 2018 ASCO-CAP recommendations for HER2 testing are affirmed.HER2 testing guidelines have focused on identifying HER2 protein overexpression or gene amplification in breast cancer to identify patients for therapies that disrupt HER2 signaling. This update acknowledges a new indication for trastuzumab deruxtecan when HER2 is not overexpressed or amplified but is immunohistochemistry (IHC) 1+ or 2+ without amplification by in situ hybridization. Clinical trial data on tumors that tested IHC 0 are limited (excluded from DESTINY-Breast04), and evidence is lacking that these cancers behave differently or do not respond similarly to newer HER2 ADCs. Although current data do not support a new IHC 0 versus 1+ prognostic or predictive threshold for response to trastuzumab deruxtecan, this threshold is now relevant because of the trial entry criteria that supported its new regulatory approval. Therefore, while it is premature to create new result categories of HER2 expression (eg, HER2-Low, HER2-Ultra-Low), best practices to distinguish IHC 0 from 1+ are now clinically relevant. This Update affirms prior HER2 reporting recommendations and offers a new HER2 testing reporting comment to highlight the current relevance of IHC 0 versus 1+ results and best practice recommendations to distinguish these often subtle differences.Additional information is available at www.asco.org/breast-cancer-guidelines.
Genetic Underpinnings of the Transition From Alcohol Consumption to Alcohol Use Disorder: Shared and Unique Genetic Architectures in a Cross-Ancestry Sample
Authors: Rachel L. Kember, Rachel Vickers-Smith, Hang Zhou, Heng Xu, Mariela Jennings, Cecilia Dao, Lea Davis, Sandra Sanchez-Roige, Amy C. Justice, Joel Gelernter, Marijana Vujkovic, Henry R. Kranzler
Journal: American Journal of Psychiatry (2023)

Recent genome-wide association studies (GWASs) of alcohol-related phenotypes have uncovered key differences in the underlying genetic architectures of alcohol consumption and alcohol use disorder (AUD), with the two traits having opposite genetic correlations with psychiatric disorders. Understanding the genetic factors that underlie the transition from heavy drinking to AUD has important theoretical and clinical implications.
Melanoma In Situ—Getting the Diagnosis and Prognosis Right
Authors: Anne E. Cust, Richard A. Scolyer
Journal: JAMA Dermatology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal